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The handful of companies pursuing CRAC inhibitors for immunological
disorders have a new indication to consider-acute pancreatitis. New findings
from Cardiff University1 show that the
target plays a central role in the painful and potentially life-threatening
condition for which there are no FDA-approved, disease-modifying therapies.

Binge
drinking can trigger acute pancreatitis, in which excessive release of pancreatic
enzymes leads to pain, inflammation and damage to pancreatic tissue.

Treatment
focuses on alleviating pain and inflammation or on managing rare metabolic
conditions that bring on bouts of the disorder independently of binge drinking.
For example, Glybera alipogene tiparvovec (AMT-011), a gene therapy from uniQure B.V., is approved in the EU to treat lipoprotein lipase (LPL) deficiency, a hereditary condition
that leads to acute, recurring pancreatitis.

The
Cardiff team, led by professor and director of biosciences Ole Petersen, now
has evidence in cell culture that blocking the CRAC (calcium release-activated calcium
channel) can prevent the toxicity and cell death that lead to
tissue damage in pancreatitis.

"To
date, CRAC has been detected in numerous different tissues, but since most
tissues outside of the immune system possess other channels that can provide
intracellular calcium at suitable levels, CRAC has only been [thought to be]
essential for the function of lymphocytes," said Christian Cortis, head of
business development at Synta. "These results are novel in that they
appear to identify another cell type with significant dependence on CRAC."

CRACkdown

Petersen said his team had suspected for
some time that deranged calcium release played a role in acute pancreatitis,2
but it was not clear until now which types of calcium channels were involved.

"We
made the original hypothesis in the early 1990s that pancreatitis might be a
calcium toxicity disease," said Petersen. "There's no doubt that an
early step in pancreatitis is calcium channel release from internal stores in
response to high concentrations of bile acids or alcohol-related compounds."

In
the new study, Petersen's team used in vitro pharmacology and
electrophysiology to show that CRAC was involved in normal regulation of
calcium in pancreatic cells. GSK-7975A, a CRAC antagonist,
blocked the influx of calcium into cultured murine acinar cells depleted of
intracellular calcium stores.

GSK-7975A
was originally developed by GlaxoSmithKline plc's respiratory
disease unit as a research tool.

The
Cardiff team then used an in vitro assay of acinar cell activity in
which exposure to fatty acid ethyl esters, a toxic metabolite of fat and
alcohol, led to high calcium spikes, excessive enzyme release and cell death.

"We
expose cells isolated from mice to a combination of fatty acids and alcohol, a
scenario that we think the cells would experience in an alcoholic binge,"
said Petersen.

Results
were reported in the Proceedings of the National Academy of Sciences and
were not patented.

CRAC
pipeline

Petersen's electrophysiological studies,
together with previous genetic studies of hereditary mutations in components of
the CRAC complex, suggest the target is likely not required for normal
pancreatic secretion and becomes activated only in extreme situations such as
alcohol overexposure.

"The
absolute dependence of the pancreatic acinar cells on CRAC in vivo has
yet to be established," said Cortis. "The absence of digestive
problems in children with genetically defective CRACM1 protein may suggest that
at least CRACM1 is not essential for normal functioning of the human pancreas."
Petersen's laboratory is undertaking animal studies to establish whether
blocking CRAC can prevent acute pancreatitis in vivo.

Petersen
said current animal models of pancreatitis do not respond to alcohol exposure,
making it difficult to develop therapies for alcohol-induced pancreatitis.

"The
majority of people in this field have used a hyperstimulation model, in which
you treat [rodents] with high doses of the hormones that normally elicit
pancreatic secretion," said Petersen. "The reason that people have
stuck with hyperstimulation is that giving alcohol by itself doesn't do very
much."

Petersen
suspects that animals will more readily develop pancreatitis when treated with
a combination of fatty acids and alcohol, which combine to form fatty acid
ethyl esters. "We think it's quite important that there also be a high-fat
diet as well as alcohol," he said.

An
open question is whether other calcium channels besides CRAC play a role in
acute pancreatitis.

"This
paper provides good evidence for a role for CRAC in acute pancreatitis. There
is evidence that GSK-7975A works, so it looks and smells like CRAC, but it
would be good to test other compounds" that block other calcium channels,
said Kenneth Stauderman, VP of research at CalciMedica.

What
is also missing is evidence that the CRAC components found in rodent acinar
cells are present in the human pancreas and are activated in acute
pancreatitis.

Stauderman
and CalciMedica president and CEO Gonul Velicelebi noted that the specific
subunits of CRAC in pancreatic cells may differ from those in immune cells. In
human T cells, the principal components of CRAC are CRACM1 and STIM1, but
alternative variants of both proteins are known to exist.

"CRACM comes in three flavors, but CRACM1
is apparently the most important for immune cell functions. STIM exists in two forms, but STIM1 is
the most relevant in T cells," said Velicelebi. "We don't know the
selectivity of the GSK compound for CRACM1 versus other variants."

To
establish that CRACM1 and STIM1 are the relevant players in acinar cells, she
suggested knocking down either protein and testing whether it leads to an
effect similar to that of GSK-7975A.

CalciMedica
is developing CRACM1 inhibitors for a range of autoimmune and inflammatory
diseases. Last year, the company discontinued its Phase I psoriasis candidate, cm2489, and plans to put a
more potent backup compound into Phase I testing next year.

Synta's preclinical CRACM1 antagonists, STA-12-7525
and STA-12-8336,
were discovered in a now-ended collaboration with Roche. Cortis said Synta
has full rights to the compounds, which are not undergoing further development
and are available for out-licensing.

Cortis,
Stauderman and Velicelebi all noted that Petersen's study suggests their
respective companies' compounds could be tested in pancreatitis but said they
did not currently plan to do so.

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